title: Regulation of p53 by jagged1 contributes to angiotensin II-induced impairment of myocardial angiogenesis.
abstract: Angiotensin II (AngII) is a major contributor to the development of heart failure, however, the molecular and cellular mechanisms still remain elucidative. Inadequate angiogenesis in myocardium leads to transition from cardiac hypertrophy to dysfunction, this study was therefore conducted to examine the effects of AngII on myocardial angiogenesis and the underlying mechanisms. AngII treatment significantly impaired angiogenetic responses, which were determined by counting the capillaries either in matrigel formed by cultured cardiac microvascular endothelial cells (CMVECs) or in myocardium of mice and by measuring the in vitro and in vivo production of VEGF proteins, and stimulated accumulation and phosphorylation of cytosolic p53 which led to increases in phosphorylated p53 and decreases of hypoxia inducible factor (Hif-1) in nucleus. All of these cellular and molecular events induced by AngII in CEMCs and hearts of mice were largely reduced by a p53 inhibitor, pifithrin-α (PFT-α). Interestingly, AngII stimulated the upregulation of Jagged1, a ligand of Notch, but it didn't affect the expression of Delta-like 4 (Dll-4), another ligand of Notch. Inhibition of p53 by PFT-α partly abolished this effect of AngII. Further experiments showed that knockdown ofJagged1 by addition of siRNA to cultured CMVECs dramatically declined AngII-stimulated accumulation and phosphorylation of p53 in cytosol, upregulation of phosphorylated p53 and downregulation of Hif-1 expression in nucleus, decrease of VEGF production and impairment of capillary-like tube formation by the cells. Our data collectively suggest that AngII impairs myocardial angiogenetic responses through p53-dependent downregulation of Hif-1 which is regulated by Jagged1/Notch1 signaling.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China ; Department of Cardiology, Qingdao Municipal Hospital, Qingdao, China.
authors.forename: Aili
authors.initials: A
authors.lastname: Guan
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
authors.forename: Jianguo
authors.initials: J
authors.lastname: Jia
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhang
authors.forename: Bingyu
authors.initials: B
authors.lastname: Li
authors.forename: Chunjie
authors.initials: C
authors.lastname: Yang
authors.forename: Sanli
authors.initials: S
authors.lastname: Qian
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Ruizhen
authors.initials: R
authors.lastname: Chen
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D007797:Laminin / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D061251:Primary Cell Culture; D011509:Proteoglycans / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D002135:Calcium-Binding Proteins; D004338:Drug Combinations; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D007797:Laminin; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D011509:Proteoglycans; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D016159:Tumor Suppressor Protein p53; D000804:Angiotensin II; C059485:matrigel; D014050:Toluene; D003094:Collagen; C121565:pifithrin